Abstract
The replication of small DNA viruses requires both host DNA replication and repair factors that are often recruited to subnuclear domains termed viral replication centers (VRCs). Aside from serving as a spatial focus for viral replication, little is known about these dynamic areas in the nucleus. We investigated the organization and function of VRCs during murine polyomavirus (MuPyV) infection using 3D structured illumination microscopy (3D-SIM). We localized MuPyV replication center components, such as the viral large T-antigen (LT) and the cellular replication protein A (RPA), to spatially distinct subdomains within VRCs. We found that viral DNA (vDNA) trafficked sequentially through these subdomains post-synthesis, suggesting their distinct functional roles in vDNA processing. Additionally, we observed disruption of VRC organization and vDNA trafficking during mutant MuPyV infections or inhibition of DNA synthesis. These results reveal a dynamic organization of VRC components that coordinates virus replication.
Highlights
Viruses utilize cellular proteins and signaling pathways in order to replicate, often creating new domains in the infected cell [1,2,3,4,5,6,7,8,9]
We found that viral replication center components were organized into at least two spatially and functionally distinct subdomains, and that viral DNA sequentially associated with these subdomains post-synthesis
Proteins involved in cellular DNA replication and repair have been previously localized to viral replication centers (VRCs) during murine polyomavirus (MuPyV) infection, and a subset of these proteins are required for viral genome replication [7,8]
Summary
Viruses utilize cellular proteins and signaling pathways in order to replicate, often creating new domains in the infected cell [1,2,3,4,5,6,7,8,9] These virus-associated domains are a critical component of the host-pathogen interaction, and their study has informed our understanding of viral replication, as well as the cellular processes that are enlisted to enable infection [10]. We investigated one such domain, termed viral replication centers (VRCs), that form in the nucleus during murine polyomavirus (MuPyV) infections [7,8]. Mutant viruses have been used to analyze these protein interactions and have supported roles for ST and MT in genome replication and virus assembly [8,21,22,23]
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